Control of proliferation and apoptosis in cancer cells

Abstract

The invention includes a method of inhibiting or reducing cellular proliferation through the use of one or more agents that prevent the association or interaction of pp32 polypeptides with the hyperphosphorylated form of Retinoblastoma protein. The invention also discloses agents that are useful in preventing the association or interaction of pp32 polypeptides with the hyperphosphorylated form of Retinoblastoma protein. The invention also discloses screening assays that utilize pp32 polypeptide fragments to identify candidate agents useful in preventing the association or interaction of pp32 polypeptides with the hyperphosphorylated form of Retinoblastoma protein. The invention further discloses diseases and/or disorders for which the disclosed compositions and methods are useful.

1 . A method of controlling proliferation of a cell population comprising administering at least one agent that inhibits the association of pp32 with hyperphosphorylated Retinoblastoma protein (pRb).  
     
     
         2 . The method of  claim 1 , wherein said agent is administered in an amount sufficient to promote apoptosis within said cell population or to reduce E2F1-mediated transcription.  
     
     
         3 . The method of  claim 1 , wherein said agent that inhibits the association of pp32 with pRb is a peptide.  
     
     
         4 . The method of  claim 3 , wherein said peptide comprises the peptide of SEQ ID NO:3.  
     
     
         5 . The method of  claim 3 , wherein said peptide comprises a fragment of the peptide of SEQ ID NO:3, and wherein said fragment of the peptide of SEQ ID NO:3 inhibits the association of pp32 with phosphorylated Retinoblastoma protein, and wherein amino acid Thr 826  of said Retinoblastoma protein is phosphorylated.  
     
     
         6 . The method of  claim 3 , wherein said peptide is an antibody fragment.  
     
     
         7 . The method of any one of  claims 3  to  6 , wherein said peptide further comprises a nuclear localization signal.  
     
     
         8 . The method of  claim 1 , wherein amino acid Thr 826  of said Retinoblastoma protein is phosphorylated.  
     
     
         9 . The method of  claim 1 , wherein said cell population comprises tumor cells.  
     
     
         10 . The method of  claim 10 , wherein apoptosis is induced in said tumor cells.  
     
     
         11 . The method of  claim 1 , wherein said agent comprises an expression vector comprising the nucleic acid sequence of SEQ ID NO:4 operably linked to a promoter active in said cell population.  
     
     
         12 . The method of  claim 11 , wherein said expression vector is a gene therapy vector.  
     
     
         13 . The method of  claim 1 , wherein said cell population comprises neoplastic cells.  
     
     
         14 . The method of  claim 13 , wherein said neoplastic cells are prostate cancer cells.  
     
     
         15 . The method of  claim 13 , wherein said neoplastic cells are selected from the group consisting of breast, colon, lung, stomach, and pancreatic cancer cells, leukemias, lymphomas, melanomas and other skin cancer cells, and brain cancer cells including glioblastoma cells.  
     
     
         16 . The method of  claim 1 , wherein said agent comprises a peptidomimetic.  
     
     
         17 . A method of screening for agents that inhibit the association of pp32 with pRb, comprising (a) mixing a candidate agent with pp32 and pRb, and (b) measuring the binding of pp32 to pRb.  
     
     
         18 . The method of  claim 17 , wherein at least one of said pp32 or pRb of step (a) is provided in a cell lysate.